The candidate's long term career goal is to become an independent researcher within the field of pharmacotherapy development for cognitive enhancement in substance-abusing populations. A multidisciplinary mentoring program is proposed that will help assist the transition to independent research by providing structured supervision and didactic techniques in a) the conduct and assessment of pharmacotherapy development trials, b) a theoretical and practical understanding of the neurobiological and pharmacological basis of cognition and addiction, and c) data analytical techniques relevant to pharmacotherapy trials with multiple time-points and outcomes. Cocaine dependence is one of the most common and preventable health care problems in the US. Most importantly, cognitive difficulties associated with cocaine dependence may represent unique targets for pharmacotherapy intervention as they may reflect relapse-related brain changes as well as underlie goal-oriented behaviors associated with treatment outcome. While many studies have tried to elucidate the difficulties in cognition associated with cocaine dependence, relatively few studies have focused on identifying which cognitive processes represent effective targets for pharmacotherapy development and which processes are good predictors of cocaine treatment outcome. Guanfacine hydrochloride is an alpha2 adrenergic agonist, which centrally inhibits norepinephrine (NE)-related stress systems and has been shown to reduce stress-induced cocaine craving and stress-induced negative mood in cocaine dependent patients. Pharmacological agents that reduce stress system arousal and cocaine reinforcement may also impact specific cognitive processes, such as inhibitory control, due to an overlap in stress, reward and cognitive brain systems. The candidate therefore proposes to devise a battery of neurocognitive tasks that will measure inhibitory control (and associated cognitive factors), will be sensitive to the enhancing effects of guanfacine and will be good predictors of treatment outcome. The proposed Mentored Research Scientist Development Award (MRSDA) project will add a neurocognitive battery onto a currently funded nine week (3 weeks inpatient and 6 weeks outpatient) double blind, placebo controlled treatment trial assessing the pharmacotherapeutic effects of guanfacine dose. This will provide the candidate with the infrastructure to test a group of ninety cocaine dependent individuals on a neurocognitive battery both at baseline and following three weeks of inpatient guanfacine treatment. In addition, a subsequent six week outpatient trial will allow the candidate to assess relapse and relapse factors as a function of cognitive improvement. The potential for specific pharmacological agents to ameliorate cognitive processes that may underpin goal-directed behaviors including impulsivity, self-monitoring decision-making may be critical to reducing risk of relapse and thus have a wide ranging impact on individual welfare and societal health care costs. Through the structured training opportunity afforded by the K01 MRSDA the candidate will be able to develop a productive program of research focused on identifying salient cognitive processes for pharmacotherapy development in substance abusing disorders. PUBLIC HEALTH RELEVANCE: There is a pressing need not only to develop new pharmacotherapies for cocaine dependence, but also to identify easily quantifiable targets for measuring treatment efficacy. Difficulties in selective cognitive processes may reflect brain system changes involved in cocaine reinforcement as well as underlie goal-oriented behaviors associated with changes in substance abuse behavior. These include impulsivity, self-regulation and decision making. As such, decrements in selective cognitive processes, such as inhibitory control, may represent efficacious targets for pharmacotherapy intervention as well as important mediators of cocaine treatment outcome. As guanfacine has been shown to decrease stress-induced sympathetic arousal and stress-induced cocaine craving, we suggest that it may also improve certain cognitive processes, due to an overlap in stress, reward and cognitive brain systems. The objectives of the current proposal are therefore to select a battery of neurocognitive tests that will be sensitive to the enhancing effects of guanfacine hydrochloride treatment in cocaine dependent inpatients, and which may also be good predictors of cocaine relapse and relapse factors during outpatient treatment. As poor cognitive function may underlie so many behavioral processes sub-serving addiction, ameliorating these difficulties with pharmacological agents may serve to reduce relapse vulnerability and thus many of the debilitating symptoms of cocaine dependence. Training junior scholars to proficiency with regard to the conduct of cognitive pharmacotherapy development research is therefore critical to improving the health and welfare of vulnerable and addicted populations.